Macrolide antibiotics, characterized by a large lactone ring to which are attached one or more deoxy sugars, usually cladinose and desosamine, are antimicrobial drugs that are active against aerobic and anaerobic gram positive cocci and are prescribed for the treatment of a number of infections, including respiratory tract and soft tissue infections. The macrolides, which belong to the polyketide class of natural products, function by reversibly binding to the 50S subunit of the bacterial ribosome, blocking protein synthesis and preventing bacterial growth and reproduction. Although this action is primarily bacteriostatic, certain triazole-containing fluoroketolide macrolides are bactericidal. Other macrolides may be bactericidal at higher concentrations.
Ketolides, which are semi-synthetic derivatives of the 14-membered macrolide erythromycin A, belong to the class of drugs used to treat respiratory tract infections. These drugs are effective against macrolide-resistant bacteria because of their ability to bind to two sites on the bacterial ribosome. Even so, acquired bacterial resistance to macrolides may occur, such as by post-transcriptional methylation of the 23S bacterial ribosome. This resistance results in cross-resistance to macrolides, lincosamides and streptogramins. Although rare, acquired resistance also can result from the production of drug-inactivating enzymes such as esterases or kinases, as well as the production of active ATP-dependent efflux proteins that transport macrolides out of the cell. A significant fraction of pneumococci are resistant to currently available antibiotics.
Erythromycin and the semi-synthetic derivatives azithromycin and clarithromycin are among the currently approved macrolide antibiotics. Telithromycin and cethromycin belong to the ketolide group of antibiotics. Oral administration has been accomplished for many macrolides and ketolides, including erythromycin, clarithromycin, telithromycin, and azithromycin. Erythromycin is also formulated as a lactobionate salt for injection; azithromycin is also formulated as a citrate salt for injection; and clarithromycin is available in some countries formulated as a lactobionate salt for injection. Ketolides, such as telithromycin and cethromycin have not been approved for parenteral administration, including IV administration. Unlike the oral counterparts, the corresponding parenteral administration, such as intravenous (IV) and intramuscular (IM) administration of known macrolides and ketolides, especially approved macrolides such as erythromycin, clarithromycin, telithromycin, and azithromycin, has been hampered by pharmacologic pain upon administration, and adverse side effects that may arise from the substantially different pharmacokinetics and pharmacodynamics accompanying parenteral administration compared to oral administration. For example, erythromycin, clarithromycin, and azithromycin have been reported to be painful when administered parenterally, leading to limitations on their use, issues with patient compliance, and other disadvantages.
Currently, there are no ketolides approved for parenteral administration, including intravenous administration. Accordingly, a need exists for alternative parenteral formulations, and methods for using such parenteral formulations, of ketolides in the treatment of bacterial, protozoal, and other infections. In addition, a need exists for parenteral formulations, and methods for using such parenteral formulations, of ketolides that may be administered at higher concentrations, and at faster rates.
It has been unexpectedly discovered that conventional formulations, such as formulations that include lactobionate salts, citrate salts, and/or physioloigcal saline, are not readily adaptable for use with triazole-containing ketolide antibiotics. Such conventional formulations require undue optimization to provide compositions and methods for treating bacterial, protozoal, and other infections without excessive pain, or other adverse side effects. In particular, such conventional formulations may not be administered in high concentrations, or at rapid rates due to pain, or other adverse side effects.
It has also been unexpectedly discovered that formulations of triazole-containing ketolide antibiotics that include one or more lactic acids, one or more amino acids, or combinations thereof, including any pharmaceutically acceptable salts of the foregoing, are useful for the parenteral delivery of such triazole-containing ketolide antibiotics.
Illustrative triazole-containing ketolide antibiotics include compounds described in WO 2004/080391, and related compounds. Further illustrative triazole-containing ketolide antibiotics include compounds of the formula:
and pharmaceutically acceptable salts, solvates, and hydrates thereof, wherein:
R10 is hydrogen, acyl or a prodrug moiety;
X and Y are taken together with the attached carbon to form carbonyl;
V is C(O);
W is H, F, Cl, Br, I, or OH;
A is CH2, C(O), C(O)O, C(O)NH, S(O)2, S(O)2NH, or C(O)NHS(O)2;
B is C2-C10 alkenylene, or C1-C10 alkylene, such as (CH2)n where n is an integer ranging from 1-10, from 2-6, or from 3-5; and
C is hydrogen, hydroxy, acyl, acyloxy, sulfonyl, ureido, or carbamoyl, or alkyl, alkoxy, heteroalkyl, heteroalkoxy, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, each of which is optionally substituted.
Further illustrative triazole-containing ketolide antibiotics include the fluoroketolide compound solithromycin (SOL), Chemical Abstracts Registry Number 760981-83-7, and having the following structure:
and pharmaceutically acceptable salts, hydrates, solvates, esters, and prodrugs thereof. SOL is also described in international patent application, publication number WO 2004/080391. Solithromycin is also known as CEM-101 and as OP-1068. The preparation of SOL and related compounds is described in WO 2009/055557. The disclosure of each of the foregoing publications, and each additional publication cited herein are incorporated herein by reference.
Also described herein are solid, solution, and liquid formulations for such other therapeutic compounds that are characterized by low solubility and/or low basicity. It has been surprisingly discovered that the formulations described herein that include of one or more lactic acids, one or more amino acids, or combinations thereof, including any pharmaceutically acceptable salts of the foregoing, are useful for the parenteral delivery of such low solubility and/or low basicity therapeutic compounds.
Without being bound by theory, it is believed herein that the formulations described herein improve the solubility of such therapeutic compounds, including such therapeutic compounds that are weakly basic. In another embodiment, described herein are pharmaceutical compositions comprising lactic acid and pharmaceutically acceptable salts thereof adapted for the parenteral administration of low solubility and/or low basicity therapeutic compounds. In another embodiment, described herein are pharmaceutical compositions comprising amino acid and pharmaceutically acceptable salts thereof adapted for the parenteral administration of low solubility and/or low basicity therapeutic compounds. In another embodiment, described herein are pharmaceutical compositions comprising lactic acid and amino acids, and pharmaceutically acceptable salts thereof, adapted for the parenteral administration of low solubility and/or low basicity therapeutic compounds. The solid, liquid, and solution formulations described herein solve the problems of administering low solubility and/or weakly basic therapeutic compounds, such as triazole-containing macrolide antibiotics.